Ingenuity pathways analysis of urine metabonomics phenotypes toxicity of gentamicin in multiple organs
Ingenuity pathways analysis of urine metabonomics phenotypes toxicity of gentamicin in multiple organs
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DOI：
10.1039/c0mb00064g
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发表时间：
2010-01-01
影响因子：
--
通讯作者：
Chen, Xi
中科院分区：
文献类型：
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作者：
Lv, Haitao;Liu, Lian;Chen, Xi
我们介绍了使用的有害途径分析，以分析全球代谢组学，以表征表型的生化扰动和庆大霉素诱导的多器官毒性的潜在机制。对Sprague道利大鼠（200 mg/kg，n = 6）单次给予庆大霉素，并在庆大霉素给药前-24-0 h、给药后0-24、24-48、48-72和72-96 h采集尿样。通过UPLC/MS进行尿液代谢组学分析，并通过模式识别分析（Heatmap，PCA和PLS-DA）对检测到的代谢物的质谱信号进行系统解卷积和分析，揭示了庆大霉素毒性诱导的生化扰动的时间依赖性。结果表明，庆大霉素毒性在动物体内引起的整体代谢组学变化是特征性的。在尿液中鉴定出几种参与氨基酸代谢的代谢物，并证实可从这些生物标志物中预测庆大霉素的生化扰动。众所周知，庆大霉素在实验室大鼠中引起多器官系统的毒性。基于知识证明的损伤途径分析显示，庆大霉素诱导了肝脏和心脏毒性，沿着先前已知的肾脏毒性。代谢产物肌酸、烟酸、前列腺素E2和胆酸被鉴定并验证为庆大霉素诱导毒性的表型生物标志物。总之，代谢组学分析在药物毒性评价中的应用的重要性再次被强调;此外，这项工作表明了有害途径分析对药物毒性研究的强大预测潜力，以及其对基于代谢组学的药物毒性评价的有价值的补充。
We introduce the use of Ingenuity Pathway Analysis to analyzing global metabonomics in order to characterize phenotypically biochemical perturbations and the potential mechanisms of the gentamicin-induced toxicity in multiple organs. A single dose of gentamicin was administered to Sprague Dawley rats (200 mg/kg, n = 6) and urine samples were collected at -24-0 h pre-dosage, 0-24, 24-48, 48-72 and 72-96 h post-dosage of gentamicin. The urine metabonomics analysis was performed by UPLC/MS, and the mass spectra signals of the detected metabolites were systematically deconvoluted and analyzed by pattern recognition analyses (Heatmap, PCA and PLS-DA), revealing a time-dependency of the biochemical perturbations induced by gentamicin toxicity. As result, the holistic metabolome change induced by gentamicin toxicity in the animal's organisms was characterized. Several metabolites involved in amino acid metabolism were identified in urine, and it was confirmed that gentamicin biochemical perturbations can be foreseen from these biomarkers. Notoriously, it was found that gentamicin induced toxicity in multiple organs system in the laboratory rats. The proof-of-knowledge based Ingenuity Pathway Analysis revealed gentamicin induced liver and heart toxicity, along with the previously known toxicity in kidney. The metabolites creatine, nicotinic acid, prostaglandin E2, and cholic acid were identified and validated as phenotypic biomarkers of gentamicin induced toxicity. Altogether, the significance of the use of metabonomics analyses in the assessment of drug toxicity is highlighted once more; furthermore, this work demonstrated the powerful predictive potential of the Ingenuity Pathway Analysis to study of drug toxicity and its valuable complementation for metabonomics based assessment of the drug toxicity.